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An efficient one-step regiospecific synthesis of novel isoxazolines and isoxazoles of N-substituted saccharin derivatives through solvent-free microwave-assisted [3+2] cycloaddition
Tetrahedron Letters 48 (2007) 443–447
An efficient one-step regiospecific synthesis of novel isoxazolines and isoxazoles of N-substituted saccharin derivatives through solvent-free microwave-assisted [3+2] cycloaddition Mahmoud Mabrour,a Khalid Bougrin,a,* Rachid Benhida,b Andre´ Loupyc and Mohamed Soufiaouia a
Laboratoire de Chimie des Plantes et de Synthe`se Organique et Bio-organique, Universite´ Mohammed V-Agdal, Faculte´ des Sciences, B.P. 1014 R.P. Rabat, Morocco b Laboratoire de Chimie des Mole´cules Bioactives et des Aroˆmes, Institurt de Chimie de Nice, UMR 6001 CNRS, Universite´ de Nice Sophia-Antipolis Parc Valrose, 06108 Nice Cedex 2, France c Laboratoire des Re´actions Se´lectives sur Supports, ICMMO, Universite´ Paris XI, 91405 Orsay Cedex, France Received 1 September 2006; revised 9 November 2006; accepted 10 November 2006 Available online 30 November 2006
Abstract—Novel isoxazolines and isoxazoles of N-substituted saccharin derivatives are synthesized in good yields by 1,3-dipolar cycloaddition of N-allyl or propargyl N-substituted saccharin with arylnitrile oxide under solvent-free microwave irradiation. In this process, the yields were significantly improved over conventional heating, without alteration of the selectivity. The regioselectivity as well as the nonthermal specific microwave effect are discussed. Ó 2006 Elsevier Ltd. All rights reserved.
There has been a gradual change from classical reaction conditions to more environmentally friendly routes.1 This growth of green chemistry holds significant potential for reduction of the by-products and in waste production and lowering of energy costs. Microwave (MW) irradiation is now used in a lot of chemical transformations for the synthesis of various compounds.2 The most evident improvements are reduced reaction time and cleaner reactions due to less side products. The intermolecular [3+2] cycloaddition reaction of arylnitrile oxides with various alkenes and alkynes represent an efficient and convergent method for the construction of isoxazoline and isoxazole rings.3 Recently, our research was focused on the application of microwave activation in organic synthesis, particularly in 1,3-dipolar cycloaddition reaction. Carrying out reactions using solvent-free conditions and under microwave irradiation,4 as opposed to conventional heating, has the advantage to increase the reaction rates because of the rapid core heating associated with microwaves Keywords: 1,3-Dipolar cycloaddition; Microwave activation; Regiocontrolled process; Arylnitrile oxide; Saccharin analogs. * Corresponding author. Tel./fax: +212 37 77 54 40; e-mail: [email protected] 0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2006.11.067
and to a possible intervention of specific nonpurely thermal effects connected to medium polarities and mechanisms.2 Functionalized isoxazoline and isoxazole derivatives are active pharmacophores in several pharmacologically important molecules,5 and are also useful intermediates for the synthesis of a wide variety of bioactive natural products.6 Furthermore, the chemistry of saccharin and analogues has been a focus of intense research, due to their widespread occurrence in nature and their diversified biological activities.7 N-Substituted saccharin derivatives have been extensively studied7,8 but to the best of our knowledge there is no report of any incorporating an isoxazoline or isoxazole moiety. As part of our continued interest in the development of efficient methods for the synthesis of heterocyclic compounds of biological importance, we report herein a straightforward access to novel isoxazoline and isoxazole N-substituted saccharin derivatives via a one-pot 1,3-dipolar cycloaddition reaction, by using microwave activation under solvent-free conditions, in the presence of a simple and inexpensive catalyst (NCS/Al2O3). We have examined the 1,3-dipolar cycloaddition reactions of N-allyl and N-propargyl saccharin as dipolarophiles (Scheme 1)
444
M. Mabrour et al. / Tetrahedron Letters 48 (2007) 443–447
O
DMF/NaOH 100-150 ˚C
NH S O2 1
acterized by spectral analysis and by comparison of their physical characteristics with those of authentic samples.
O
Br
N S O2 O
2
N S O2
3
Br
Scheme 1.
with arylnitrile oxides generated in situ from aromatic oximes precursors under conventional conditions (method A)9 and microwave irradiation (method B), for the construction of isoxazoline and isoxazole rings 4 and 5, respectively (Scheme 2). First, the required dipolarophiles 2 and 3 were, respectively, prepared by N-allylation and N-propargylation of saccharin 1 (Scheme 1). The preparation of alkyl derivatives of saccharin has been previously reported using the sodium salt of saccharin with an alkyl halide. However, this procedure gave poor yields and generally required long reaction times, which is partially due to an inadequate solvent for this type of reaction.10 Indeed, in our investigation, dimethylformamide was found to be an excellent solvent for the reaction of allyl and propargyl bromide with saccharin, in the presence of NaOH as the base. DMF is especially effective in this reaction for weakening the bromine–carbon bond. The N-allyl and N-propargyl saccharins 2 and 3 were obtained in 80% and 78% yield, respectively. The reaction is complete after 30 min when performed at a high temperature (100–150 °C). The obtained products 2 and 3 were charAr C N H
OH
Ar : a: C6H5, b: p-MeC6H4, c: p-MeOC6H4, d: p-ClC6H4, e: p-NO2C6H4, f: o-ClC6H4, g: 3,4-(NO2)C6H3 conditions B NCS./Al2O3 3 min, 1000W, 110-150 ˚C
conditions A NaOClaq./CH2Cl2 0-5 ˚C, 5 h
Ar C N Cl
As indicated by the results in Table 1 and Scheme 2, it appears that solvent-free and microwave activation on NCS/alumina is an efficient and more adaptable conditions for the synthesis of 4 and 5 like series. The structures of adducts 4 and 5 were confirmed through spectral analysis.
base or Δ Ar C N O in situ
2 or 3
4
6 7
O 3a 7a
3 2 1N
S O2
4 or 5
Scheme 2.
Then, reactions under solvent-free conditions were conducted using a domestic microwave oven and dipolarophiles 2 or 3 as models. The duration of irradiation at maximal power (1000 W) was systematically varied to optimize the reaction conditions. Although manufacturers of microwave-heating apparatus have directed their research to make microwaves a safe source of heating, uncontrolled reaction conditions may result to undesirable effects.4a As depicted in Table 1, microwave irradiation for 3 min was found to be the best conditions for this type of cycloaddition. Thus, the cycloaddition involving dipolarophile 2 or 3 and arylnitrile oxides furnished the desired isoxazolines 4 or isoxazoles 5, respectively, in high yields (81–95%), greatly improved when compared to the conventional method. Moreover, by using microwave activation, the reaction time was considerably decreased 100-fold. It is noteworthy that, in all cases TLC analysis indicated a complete conversion and formation of only one regioisomer without any post-isomerization compared to the classical conditions. The use of microwaves highly disfavored the dimerization process of arylnitrile oxides and this observation is rarely mentioned.4,12
OH
unstable - normally converted in situ to dipole
5
Dipolarophiles 2 and 3 were then treated with various arylnitrile oxides under usual conditions with aqueous NaOCl in methylene chloride (method A)9 or under solvent-free microwave activation using NCS impregnated on alumina (method B). When reacting 2 or 3 with arylnitrile oxides using classical conditions, the dimerization of nitrile oxide into furoxan9a derivatives was the predominant reaction, lowering therefore the cycloaddition reaction yield. In our experiments, the furoxan dimer was isolated in the case of benzaldoxime.9,11 Therefore, a search was made for the optimum conditions which would disfavor the competitive dimerization process. As shown in Table 1, when arylnitrile oxide was generated over 5 h, the cycloaddition reaction of arylnitrile oxide with dipolarophiles 2 or 3, under conventional conditions, provided cycloadducts in low to moderate yields (14–45%, Table 1). The cycloadducts 4 or 5 were obtained with a regiocontrol as expected in the literature.13
1 5' 1'O
4' 3'
N
2'
Ar
The IR absorptions of compound 4a at mmax = 1635 cm1 indicated the existence of the isoxazoline C@N group. The 1H NMR spectrum of 4a showed a multiplet centred at d 5.23 ppm for the CH stereogenic centre and two doublets of doublets at d 3.37 and d 3.50 ppm for C4 0 HaHb protons. The N–CH2 protons resonated as two doublets of doublets at d 3.9 and 4.08 ppm. The aromatic proton exhibited a multiplet at d 7.41– 7.96 ppm. The 13C NMR spectrum of 4a exhibited a
M. Mabrour et al. / Tetrahedron Letters 48 (2007) 443–447
445
Table 1. Formation of isoxazolines 4 and isoxazoles 5 under conventional and solvent-free conditions Product
Conventional conditions Time (h)
4a 4b 4c 4d 4e 4f 4g 5a 5b 5c 5d 5e 5f 5g
5 5 5 5 5 5 5 5 5 5 5 5 5 5
Yielda (%) b
20(79) 45 40 37 30 32 26 12 37 32 28 25 20 14
Solvent-free conditions Time (min)
Temperaturec (°C)
Yieldd (%) [MW]
Yielde (%) [triangle]
3 3 3 3 3 3 3 3 3 3 3 3 3 3
130 150 120 110 130 124 136 120 140 112 111 119 116 130
91 95 93 98 92 94 90 81 90 88 93 87 85 83
0 Trace Trace 2 3 <2 5 0 2 3 Trace Trace Trace 4
a
Yield of isolated product under stirring (method A): dipolarophiles 2 or 3 (1 mmol), arylaldoxime (1.2 mmol), aq NaOCl, CH2Cl2, 5 to 0 °C. Yield of the isolated furoxan (white crystalline solid, mp 114–116 °C). c Evaluated temperature at the end of the reaction (infrared detection and a digital thermometric probe). d Yield of isolated product under microwave (1000 W, 3 min) (method B): dipolarophiles 2 or 3 (1 mmol), arylaldoxime (1.2 mmol), NCS, Al2O3. e Yield of isolated product obtained with classical heating (n) under same reaction conditions (3 min, final temperature, and atmospheric pressure) determined under microwave irradiation. b
signal at 39.02 ppm corresponding to N–CH2 carbon and two peaks at 41.94 and 77.53 ppm relative to C4 0 and C5 0 isoxazoline carbons. The C@N and carbonyl carbons C3 0 and C3 resonated at 156.66 and 159.53 ppm, respectively. The structure of 4a was further confirmed by mass spectrometry. Similarly, the IR spectrum of compound 5a showed an absorption at mmax = 1611 cm1 due to the isoxazole C@N bond. The 1H NMR spectrum of 5a showed a singlet at d 5.08 ppm for the N–CH2 protons. The C4–H isoxazole proton resonated as a sharp singlet at d 6.68 ppm, and the aromatic proton as a multiplet at d 7.42–8.13 ppm. The 13C NMR spectrum of 5a showed one signal at d 33.88 ppm for the N–CH2 carbon and two peaks at d 102.39 and 162.93 ppm for the two characteristic isoxazole carbons C4 and C5 0 , respectively. The C@N and carbonyl carbons C3 0 and C3 resonated at d 158.65 and 165.96 ppm, respectively. Mass spectrometry is also in accordance with the proposed structure for 5a.
compared to the other transition states. Otherwise, when considering the structure of 2a, the charge densities (0.17 and 0.18) and the atomic coefficients in p* orbital (0.47 and 0.48), respectively, on the two carbon atoms of the double bond, one cannot predict any difference in the two attacks. One can finally assume that the preference for attack leading to 4a is connected simply to the steric control of the reaction.
The regioselectivity observed is in accordance with the one normally found in nitrile oxide cycloaddition with terminal alkenes and alkynes.13 To get further insight into the factors responsible for the regioselectivity observed here, we performed calculations using the PM3 method14 as implemented in the software available from ChemDraw 3D, version 4.0. We have thus checked the values of standard enthalpy formations DH 0f of final products 4a and 6a as well as of starting materials 2 and phenylnitrile oxide. After full geometry optimizations, the two possible transition states were considered leading to either 4a or 6a (Scheme 3). The main results are given in Table 2. It is clear that the pathway leading to 4a is favored, as the energy of activation is lower by 0.86 kcal/mol when
Scheme 3. The two possible transition states for the cycloaddition of phenylnitrile oxide and allyl saccharin.
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M. Mabrour et al. / Tetrahedron Letters 48 (2007) 443–447
Table 2. PM3 calculations of reagents, products and transition states (TS) DH 0f a Phenylnitrile oxide Allyl saccharin 2 Cycloadduct 4a Cycloadduct 6a TS toward 4a TS toward 6a
55.57 54.34 27.40 23.28 37.44 38.30
E act.b
lc
36.21 37.07
2.57 3.65 6.97 6.98 4.83 3.60
a
Standard enthalpy formation in kcal/mol. Energy of activation in kcal/mol. c Dipole moment in Debyes. b
Finally, in order to check the possible intervention of specific (nonthermal) microwave effects,2,15 the best results obtained under microwave irradiation were extrapolated to conventional heating by carrying out the reactions under similar conditions (time, temperature, pressure, and vessel). It was found that the reaction did not occur and the reactants remained unchanged even on extended reaction times (Table 1), thus suggesting that the effect of microwaves is not simply thermal.2,16,17 The nonthermal MW effects evidenced here can be easily explained by considering the evolution of polarities between ground state and transition state. The values of dipole moments as given in Table 2 clearly indicate that the polarity is significantly increased from starting materials toward transition state and even toward the final product. Indeed, as the polarity is enhanced with the reaction progress, the dipole–dipole stabilization with the electric field is increased and consequently a positive MW effect is expected.2,17 In conclusion, we have developed, by coupling solventfree conditions and microwave assistance, a new, efficient and green method for the synthesis of novel isoxazoline and isoxazole N-substituted saccharins. The process involves regiospecific [3+2] cycloaddition between alkenes or alkynes and arylnitrile oxides. The biological activity and inhibitory effect of such analogues against human leukocyte elastase (HLE), cathepsin G (Cat G), and proteinase 3 (PR 3) is under examination. Acknowledgments We acknowledge CNRS-CNRST (convention d’e´change France-Maroc CHIMIE 04/06), Re´gion PACA and Ministry of Education, Government of Morocco (PROTARS III, D13/57) for financial support. We are especially thankful to Dr. F. Maurel (Itodys, Universite´ Paris VII) for the theoretical calculations. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.tetlet. 2006.11.067.
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9. (a) Yu, Z.-X.; Houk, K. N. J. Am. Chem. Soc. 2003, 125, 13825; (b) Lee, G. Synthesis 1982, 508. 10. (a) Lyashchenko, G. S.; Medvedeva, A. S.; Safronova, L. P.; Bannikova, O. B.; Voronkov, M. G. Bull. Acad. Sci. USSR Div. Chem. Sci. 1991, 12, 2520; (b) Inoue, Y.; Taguchi, M.; Toyofuku, M.; Hashimoto, H. Bull. Chem. Soc. Jpn. 1984, 57, 3021; (c) Dahlbom, R.; Karle´n, B.; George, R.; Jenckn, D. J. J. Med. Chem. 1966, 9, 843; (d) Rice, H. L.; Pettit, G. R. J. Am. Chem. Soc. 1954, 76, 302; (e) Merritt, L. L.; Levey, J. S.; Cutter, H. B. J. Am. Chem. Soc. 1939, 61, 15. 11. (a) Radhakrishna, A. S.; Sivaprakash, K.; Singh, B. B. Synth. Commun. 1991, 21, 1625; (b) Whitney, R. A.; Nicholas, E. S. Tetrahedron Lett. 1981, 35, 3371; (c) Grundmann, C. Synthesis 1970, 344; (d) Grundmann, C.; Datta, S. J. Org. Chem. 1969, 2016. 12. Lu, T.-J.; Tzeng, G.-M. J. Chin. Chem. Soc. 2000, 47, 189. 13. (a) Shu, C.-M.; Lin, W.-L.; Lee, G.-H.; Peng, S.-M.; Chung, W.-S.; Wu, S.-H. J. Chin. Chem. Soc. 2000, 47, 173; (b) Kurth, M. J.; Schore, N. E.; Beebe, X. J. Org.
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An efficient one-step regiospecific synthesis of novel isoxazolines and isoxazoles of N-substituted saccharin derivatives through solvent-free microwave-assisted [3+2] cycloaddition Mahmoud Mabrour,a Khalid Bougrin,a,* Rachid Benhida,b Andre´ Loupyc and Mohamed Soufiaouia a
Laboratoire de Chimie des Plantes et de Synthe`se Organique et Bio-organique, Universite´ Mohammed V-Agdal, Faculte´ des Sciences, B.P. 1014 R.P. Rabat, Morocco b Laboratoire de Chimie des Mole´cules Bioactives et des Aroˆmes, Institurt de Chimie de Nice, UMR 6001 CNRS, Universite´ de Nice Sophia-Antipolis Parc Valrose, 06108 Nice Cedex 2, France c Laboratoire des Re´actions Se´lectives sur Supports, ICMMO, Universite´ Paris XI, 91405 Orsay Cedex, France Received 1 September 2006; revised 9 November 2006; accepted 10 November 2006 Available online 30 November 2006
Abstract—Novel isoxazolines and isoxazoles of N-substituted saccharin derivatives are synthesized in good yields by 1,3-dipolar cycloaddition of N-allyl or propargyl N-substituted saccharin with arylnitrile oxide under solvent-free microwave irradiation. In this process, the yields were significantly improved over conventional heating, without alteration of the selectivity. The regioselectivity as well as the nonthermal specific microwave effect are discussed. Ó 2006 Elsevier Ltd. All rights reserved.
There has been a gradual change from classical reaction conditions to more environmentally friendly routes.1 This growth of green chemistry holds significant potential for reduction of the by-products and in waste production and lowering of energy costs. Microwave (MW) irradiation is now used in a lot of chemical transformations for the synthesis of various compounds.2 The most evident improvements are reduced reaction time and cleaner reactions due to less side products. The intermolecular [3+2] cycloaddition reaction of arylnitrile oxides with various alkenes and alkynes represent an efficient and convergent method for the construction of isoxazoline and isoxazole rings.3 Recently, our research was focused on the application of microwave activation in organic synthesis, particularly in 1,3-dipolar cycloaddition reaction. Carrying out reactions using solvent-free conditions and under microwave irradiation,4 as opposed to conventional heating, has the advantage to increase the reaction rates because of the rapid core heating associated with microwaves Keywords: 1,3-Dipolar cycloaddition; Microwave activation; Regiocontrolled process; Arylnitrile oxide; Saccharin analogs. * Corresponding author. Tel./fax: +212 37 77 54 40; e-mail: [email protected] 0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2006.11.067
and to a possible intervention of specific nonpurely thermal effects connected to medium polarities and mechanisms.2 Functionalized isoxazoline and isoxazole derivatives are active pharmacophores in several pharmacologically important molecules,5 and are also useful intermediates for the synthesis of a wide variety of bioactive natural products.6 Furthermore, the chemistry of saccharin and analogues has been a focus of intense research, due to their widespread occurrence in nature and their diversified biological activities.7 N-Substituted saccharin derivatives have been extensively studied7,8 but to the best of our knowledge there is no report of any incorporating an isoxazoline or isoxazole moiety. As part of our continued interest in the development of efficient methods for the synthesis of heterocyclic compounds of biological importance, we report herein a straightforward access to novel isoxazoline and isoxazole N-substituted saccharin derivatives via a one-pot 1,3-dipolar cycloaddition reaction, by using microwave activation under solvent-free conditions, in the presence of a simple and inexpensive catalyst (NCS/Al2O3). We have examined the 1,3-dipolar cycloaddition reactions of N-allyl and N-propargyl saccharin as dipolarophiles (Scheme 1)
444
M. Mabrour et al. / Tetrahedron Letters 48 (2007) 443–447
O
DMF/NaOH 100-150 ˚C
NH S O2 1
acterized by spectral analysis and by comparison of their physical characteristics with those of authentic samples.
O
Br
N S O2 O
2
N S O2
3
Br
Scheme 1.
with arylnitrile oxides generated in situ from aromatic oximes precursors under conventional conditions (method A)9 and microwave irradiation (method B), for the construction of isoxazoline and isoxazole rings 4 and 5, respectively (Scheme 2). First, the required dipolarophiles 2 and 3 were, respectively, prepared by N-allylation and N-propargylation of saccharin 1 (Scheme 1). The preparation of alkyl derivatives of saccharin has been previously reported using the sodium salt of saccharin with an alkyl halide. However, this procedure gave poor yields and generally required long reaction times, which is partially due to an inadequate solvent for this type of reaction.10 Indeed, in our investigation, dimethylformamide was found to be an excellent solvent for the reaction of allyl and propargyl bromide with saccharin, in the presence of NaOH as the base. DMF is especially effective in this reaction for weakening the bromine–carbon bond. The N-allyl and N-propargyl saccharins 2 and 3 were obtained in 80% and 78% yield, respectively. The reaction is complete after 30 min when performed at a high temperature (100–150 °C). The obtained products 2 and 3 were charAr C N H
OH
Ar : a: C6H5, b: p-MeC6H4, c: p-MeOC6H4, d: p-ClC6H4, e: p-NO2C6H4, f: o-ClC6H4, g: 3,4-(NO2)C6H3 conditions B NCS./Al2O3 3 min, 1000W, 110-150 ˚C
conditions A NaOClaq./CH2Cl2 0-5 ˚C, 5 h
Ar C N Cl
As indicated by the results in Table 1 and Scheme 2, it appears that solvent-free and microwave activation on NCS/alumina is an efficient and more adaptable conditions for the synthesis of 4 and 5 like series. The structures of adducts 4 and 5 were confirmed through spectral analysis.
base or Δ Ar C N O in situ
2 or 3
4
6 7
O 3a 7a
3 2 1N
S O2
4 or 5
Scheme 2.
Then, reactions under solvent-free conditions were conducted using a domestic microwave oven and dipolarophiles 2 or 3 as models. The duration of irradiation at maximal power (1000 W) was systematically varied to optimize the reaction conditions. Although manufacturers of microwave-heating apparatus have directed their research to make microwaves a safe source of heating, uncontrolled reaction conditions may result to undesirable effects.4a As depicted in Table 1, microwave irradiation for 3 min was found to be the best conditions for this type of cycloaddition. Thus, the cycloaddition involving dipolarophile 2 or 3 and arylnitrile oxides furnished the desired isoxazolines 4 or isoxazoles 5, respectively, in high yields (81–95%), greatly improved when compared to the conventional method. Moreover, by using microwave activation, the reaction time was considerably decreased 100-fold. It is noteworthy that, in all cases TLC analysis indicated a complete conversion and formation of only one regioisomer without any post-isomerization compared to the classical conditions. The use of microwaves highly disfavored the dimerization process of arylnitrile oxides and this observation is rarely mentioned.4,12
OH
unstable - normally converted in situ to dipole
5
Dipolarophiles 2 and 3 were then treated with various arylnitrile oxides under usual conditions with aqueous NaOCl in methylene chloride (method A)9 or under solvent-free microwave activation using NCS impregnated on alumina (method B). When reacting 2 or 3 with arylnitrile oxides using classical conditions, the dimerization of nitrile oxide into furoxan9a derivatives was the predominant reaction, lowering therefore the cycloaddition reaction yield. In our experiments, the furoxan dimer was isolated in the case of benzaldoxime.9,11 Therefore, a search was made for the optimum conditions which would disfavor the competitive dimerization process. As shown in Table 1, when arylnitrile oxide was generated over 5 h, the cycloaddition reaction of arylnitrile oxide with dipolarophiles 2 or 3, under conventional conditions, provided cycloadducts in low to moderate yields (14–45%, Table 1). The cycloadducts 4 or 5 were obtained with a regiocontrol as expected in the literature.13
1 5' 1'O
4' 3'
N
2'
Ar
The IR absorptions of compound 4a at mmax = 1635 cm1 indicated the existence of the isoxazoline C@N group. The 1H NMR spectrum of 4a showed a multiplet centred at d 5.23 ppm for the CH stereogenic centre and two doublets of doublets at d 3.37 and d 3.50 ppm for C4 0 HaHb protons. The N–CH2 protons resonated as two doublets of doublets at d 3.9 and 4.08 ppm. The aromatic proton exhibited a multiplet at d 7.41– 7.96 ppm. The 13C NMR spectrum of 4a exhibited a
M. Mabrour et al. / Tetrahedron Letters 48 (2007) 443–447
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Table 1. Formation of isoxazolines 4 and isoxazoles 5 under conventional and solvent-free conditions Product
Conventional conditions Time (h)
4a 4b 4c 4d 4e 4f 4g 5a 5b 5c 5d 5e 5f 5g
5 5 5 5 5 5 5 5 5 5 5 5 5 5
Yielda (%) b
20(79) 45 40 37 30 32 26 12 37 32 28 25 20 14
Solvent-free conditions Time (min)
Temperaturec (°C)
Yieldd (%) [MW]
Yielde (%) [triangle]
3 3 3 3 3 3 3 3 3 3 3 3 3 3
130 150 120 110 130 124 136 120 140 112 111 119 116 130
91 95 93 98 92 94 90 81 90 88 93 87 85 83
0 Trace Trace 2 3 <2 5 0 2 3 Trace Trace Trace 4
a
Yield of isolated product under stirring (method A): dipolarophiles 2 or 3 (1 mmol), arylaldoxime (1.2 mmol), aq NaOCl, CH2Cl2, 5 to 0 °C. Yield of the isolated furoxan (white crystalline solid, mp 114–116 °C). c Evaluated temperature at the end of the reaction (infrared detection and a digital thermometric probe). d Yield of isolated product under microwave (1000 W, 3 min) (method B): dipolarophiles 2 or 3 (1 mmol), arylaldoxime (1.2 mmol), NCS, Al2O3. e Yield of isolated product obtained with classical heating (n) under same reaction conditions (3 min, final temperature, and atmospheric pressure) determined under microwave irradiation. b
signal at 39.02 ppm corresponding to N–CH2 carbon and two peaks at 41.94 and 77.53 ppm relative to C4 0 and C5 0 isoxazoline carbons. The C@N and carbonyl carbons C3 0 and C3 resonated at 156.66 and 159.53 ppm, respectively. The structure of 4a was further confirmed by mass spectrometry. Similarly, the IR spectrum of compound 5a showed an absorption at mmax = 1611 cm1 due to the isoxazole C@N bond. The 1H NMR spectrum of 5a showed a singlet at d 5.08 ppm for the N–CH2 protons. The C4–H isoxazole proton resonated as a sharp singlet at d 6.68 ppm, and the aromatic proton as a multiplet at d 7.42–8.13 ppm. The 13C NMR spectrum of 5a showed one signal at d 33.88 ppm for the N–CH2 carbon and two peaks at d 102.39 and 162.93 ppm for the two characteristic isoxazole carbons C4 and C5 0 , respectively. The C@N and carbonyl carbons C3 0 and C3 resonated at d 158.65 and 165.96 ppm, respectively. Mass spectrometry is also in accordance with the proposed structure for 5a.
compared to the other transition states. Otherwise, when considering the structure of 2a, the charge densities (0.17 and 0.18) and the atomic coefficients in p* orbital (0.47 and 0.48), respectively, on the two carbon atoms of the double bond, one cannot predict any difference in the two attacks. One can finally assume that the preference for attack leading to 4a is connected simply to the steric control of the reaction.
The regioselectivity observed is in accordance with the one normally found in nitrile oxide cycloaddition with terminal alkenes and alkynes.13 To get further insight into the factors responsible for the regioselectivity observed here, we performed calculations using the PM3 method14 as implemented in the software available from ChemDraw 3D, version 4.0. We have thus checked the values of standard enthalpy formations DH 0f of final products 4a and 6a as well as of starting materials 2 and phenylnitrile oxide. After full geometry optimizations, the two possible transition states were considered leading to either 4a or 6a (Scheme 3). The main results are given in Table 2. It is clear that the pathway leading to 4a is favored, as the energy of activation is lower by 0.86 kcal/mol when
Scheme 3. The two possible transition states for the cycloaddition of phenylnitrile oxide and allyl saccharin.
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Table 2. PM3 calculations of reagents, products and transition states (TS) DH 0f a Phenylnitrile oxide Allyl saccharin 2 Cycloadduct 4a Cycloadduct 6a TS toward 4a TS toward 6a
55.57 54.34 27.40 23.28 37.44 38.30
E act.b
lc
36.21 37.07
2.57 3.65 6.97 6.98 4.83 3.60
a
Standard enthalpy formation in kcal/mol. Energy of activation in kcal/mol. c Dipole moment in Debyes. b
Finally, in order to check the possible intervention of specific (nonthermal) microwave effects,2,15 the best results obtained under microwave irradiation were extrapolated to conventional heating by carrying out the reactions under similar conditions (time, temperature, pressure, and vessel). It was found that the reaction did not occur and the reactants remained unchanged even on extended reaction times (Table 1), thus suggesting that the effect of microwaves is not simply thermal.2,16,17 The nonthermal MW effects evidenced here can be easily explained by considering the evolution of polarities between ground state and transition state. The values of dipole moments as given in Table 2 clearly indicate that the polarity is significantly increased from starting materials toward transition state and even toward the final product. Indeed, as the polarity is enhanced with the reaction progress, the dipole–dipole stabilization with the electric field is increased and consequently a positive MW effect is expected.2,17 In conclusion, we have developed, by coupling solventfree conditions and microwave assistance, a new, efficient and green method for the synthesis of novel isoxazoline and isoxazole N-substituted saccharins. The process involves regiospecific [3+2] cycloaddition between alkenes or alkynes and arylnitrile oxides. The biological activity and inhibitory effect of such analogues against human leukocyte elastase (HLE), cathepsin G (Cat G), and proteinase 3 (PR 3) is under examination. Acknowledgments We acknowledge CNRS-CNRST (convention d’e´change France-Maroc CHIMIE 04/06), Re´gion PACA and Ministry of Education, Government of Morocco (PROTARS III, D13/57) for financial support. We are especially thankful to Dr. F. Maurel (Itodys, Universite´ Paris VII) for the theoretical calculations. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.tetlet. 2006.11.067.
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